ES2392795T3 - Indoles as modulators of the nicotinic acetylcholine receptor of subtype alpha-7 - Google Patents

Abstract

A compound of List A N- [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (trifluoromethyl) -2-pyrimidinecarboxamide; N- [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (chloro) -2-pyrimidinecarboxamide; 6- [3- (Ethyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 5- (Methyloxy) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -2-pyrazinecarboxamide; 6- (Phenyloxy) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 2- [3- (Ethyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -5-pyrimidinecarboxamide; N- [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (4-methylpiperidin) -2-pyrimidinecarboxamide; 4- (1H-Pirazol-3-yl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide; 4- [4-Cyano-5- (trifluoromethyl) -1 H -pyrazol-1-yl] -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide; 4- (1,3-Thiazol-2-yl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} benzamide; 4- (4H-1, 2, 4-Triazol-4-yl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} benzamide; 4- (1H-1, 2, 4-Triazol-3-yl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} benzamide; 4- (6-Chloro-3-pyridazinyl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide; 6- (1H-1, 2, 4-Triazol-1-yl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 6- (1H-Pirazol-1-yl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; N - {[2- (Trifluoromethyl) -1H-indol-5-yl] methyl} -2, 3'-bipyridin-5-carboxamide; 6-Phenyl-N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 5-Chloro-N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} -2-pyrazinecarboxamide; 6- (Trifluoromethyl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridazinecarboxamide; 6- [2- (Methyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 5- [3- (Ethyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -2-pyrazinecarboxamide; 5- (3-Pyridinyl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -2-pyrazinecarboxamide; N- [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (N'N Dimethyl) -2-pyrimidinecarboxamide; N- [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (2, 2, 2-trifluoroethoxy) -2-pyrimidinecarboxamide; N- [(1-Methyl-2-Trifluoromethylindole-5-yl) methyl] -5- (trifluoromethyl) -2-pyrimidinecarboxamide; or a salt thereof.

Description

Indoles as modulators of the nicotinic acetylcholine receptor of subtype alpha-7

This invention relates to novel indole derivatives that have activity in the modulation of the nicotinic acetylcholine a7 receptor (nAChR). The invention also relates to the use of derivatives to treat diseases and disorders mediated by modulation of nAChR a7. In addition, the invention relates to compositions containing derivatives and processes for their preparation.

The neurotransmitter acetylcholine (ACh), by binding to cholinergic receptors, produces the opening of ion channels within the mammalian system. The central nervous system (CNS) contains two types of ACh receptor, muscarinic receptors and nAChR. NAChRs are ionic ligand-opening channels that contain five subunits (as reviews, see Colquhon et al. (1997) Advances in Pharmacology 39, 191-220; Williams et al. (1994) Drug News & Perspectives 7, 205-223 ; Doherty et al. (1995) Annual reports in Medicinal Chemistry 30, 41-50). The nAChR family of genes can be divided into two groups: those that encode subunits � and those that encode subunits a (as a review, see Karlin & Akabas (1995) Neuron 15, 1231-1244; Sargent (1993) Annu. Rev. Neurosci 16, 403-443). Three of the subunits a, a7, a8 and a9 can form functional receptors when

15 express themselves and form homooligomeric receptors.

Certain studies have indicated that neuronal nicotinic receptors play important roles in the modulation of neurotransmission, cognition, sensory inhibition and anxiety (Zarei et al. Neuroscience 1999, 88, 755-764, Frazier et al. J. Neurosci. 1998, 18 , 8228-8235, Radcliffe et al. J. Neurosci. 1998, 18, 7075-7083, Minana et al. Neuropharmacology 1998, 37, 847-857, Albuquerque et al. Toxicol. Lett. 1998, 102-103, 211- 218, Neubauer, et al. Neurology 1998, 51, 1608-1612, Stevens et al. Psychopharmacology 1998, 136, 320-327, Adler et al. Schizophrenia Bull. 1998, 24, 189-202); Thus, there has been interest in the use of compounds that modulate these receptors to treat CNS diseases.

Certain association studies (Freedman et al, Psychopharmacology (2004), 174 (1), 54-64) that demonstrate an association between the a7 locus and a sensory inhibition deficit representing an important endophenotype of

25 schizophrenia has suggested a role for a7 receptors in the etiology of schizophrenia. These inhibition deficits in patients have been reversed transiently by nicotine with a pharmacology consistent with the action through a7. In addition, in animal models, the lesion of cholinergic afferents of the forebrain or the pharmacological blockade of a7 receptors induces similar sensory inhibition deficits that can also be seen in inbred mouse strains expressing reduced levels of the a7 receptor. It has been reported that nicotine normalizes deficits in both injured animals and strains of inbred mice, again with a pharmacology compatible with a7 receptor activity. It has been reported that pharmacological blockade of a7 receptors negatively affects short-term working memory of rodents, while it has been reported that receptor activation improves performance in the same paradigm, thus involving a7 receptors as a target for cognitive empowerment.

35 The nAChR a7 are characterized by their rapid activation kinetics and high permeability to Ca2 + compared to other subtypes (Delbono et al. J. Pharmacol. Exp. Ther. 1997, 280, 428-438), and present rapid desensitization after of exposure to agonists. (Castro et al., Neurosci. Lett. 1993, 164, 137-140, Couturier et al., Neuron 1990, 5, 847-856, Alkondon et al., J. Pharmacol. Exp. Ther. 1994, 271, 494 -506). Therefore, treatment with a7 agonists can be problematic because both acetylcholine and nicotine show activation followed by blocking and / or desensitization of the receptor and, therefore, chronic treatment with an agonist can produce an apparent antagonism. In addition, it has been shown that agonists have the highest affinity for the desensitized state of the receptor and, thus, can desensitize the receptor at concentrations below the threshold for receptor activation (Briggs and McKenna. Neuropharmacology 1998 37,1095 -1102).

45 This problem can be solved by treatment with a positive allosteric modulator (PAM). PAMs increase the activation of nAChR a7 mediated by endogenous or exogenous agonists without activating the receptor on their own, that is, in the absence of agonist. Several PAMs have been presented (Lightfoot et al. Progress in medicinal chemistry 46: 131-71, 2008), WO0132619 describes indole compounds as allosteric modulators of the nicotinic receptor

According to a first aspect, the invention provides a compound from List A selected from:

N - [(2-trifluoromethyl-1H-indol-5-yl) methyl] -5- (trifluoromethyl) -2-pyrimidinecarboxamide;

N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (chloro) -2-pyrimidinecarboxamide;

6- [3- (ethyloxy) phenyl] -N - {[2- (trifluoromethyl} -1H-indol-5-yl] methyl} -3-pyridinecarboxamide;

5- (Methyloxy) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -2-pyrazinecarboxamide;

6- (phenyloxy) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 2- [3- (ethyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -5-pyrimidinecarboxamide; N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (4-methylpiperidin) -2-pyrimidinecarboxamide; 4- (1H-pyrazol-3-yl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} benzamide;

5 4- [4-Cyano-5- (trifluoromethyl) -1 H -pyrazol-1-yl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide; 4- (1,3-thiazol-2-yl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} benzamide; 4- (4H-1,2,4-triazol-4-yl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide; 4- (1H-1,2,4-triazol-3-yl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide; 4- (6-Chloro-3-pyridazinyl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide;

6- (1H-1,2,4-triazol-1-yl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 6- (1H-pyrazol-1-yl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -2,3'-bipyridin-5-carboxamide; 6-phenyl-N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 5-chloro-N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} -2-pyrazinecarboxamide;

6- (Trifluoromethyl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridazinecarboxamide; 6- [2- (Methyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 5- [3- (ethyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -2-pyrazinecarboxamide; 5- (3-iridinyl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -2-pyrazinecarboxamide; N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (N'N-dimethyl) -2-pyrimidinecarboxamide;

N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (2,2,2-trifluoroethoxy) -2-pyrimidinecarboxamide; and N - [(1-Methyl-2-Trifluoromethylindole-5-yl) methyl] -5- (trifluoromethyl) -2-pyrimidinecarboxamide;

or a salt thereof.

Compounds of List A may form pharmaceutically acceptable salts, for example, non-toxic addition salts with organic acids, such as hydrochloric, hydrobromic, hydrochloric, sulfuric and phosphoric acid, with carboxylic acids or organosulfonic acids. Examples include the salts of HCl, HBr, HI, sulfate or bisulfate, nitrate, phosphate or bisphosphate, acetate, benzoate, succinate, sucrate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate. For reports on suitable pharmaceutical salts, see Berge et al., J. Pharm. Sci., 66, 1-19, 1977; P. L. Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; and Bighley et al., Encyclopedia of Pharmaceutical

30 Technology, Marcel Dekker Inc, New York, 1996, volume 13, pp. 453-497.

In one embodiment, the salt of the List A compound is a pharmaceutically acceptable salt.

Hereinafter, the compounds of List A and their pharmaceutically acceptable salts will be cited as "the compounds of the invention".

The compounds of the invention may be present in the form of solvate or hydrate.

The compounds of the invention or solvates / hydrates of the compounds or salts may be present in one or more polymorphic forms.

Certain compounds of the invention may be present in one or more tautomeric forms. Within the scope of the present invention all tautomers and mixtures thereof are included. Certain compounds of the invention may have one or more chiral centers and therefore may exist in various stereoisomeric forms. The

Compounds having a chiral center may be present as enantiomers or as a racemic mixture containing enantiomers. Compounds that have two or more chiral centers may be present as diastereoisomers or enantiomers. Therefore, all stereoisomers (for example enantiomers and diastereoisomers) and mixtures thereof are included within the scope of the present invention. The racemic mixtures can be separated to give their individual enantiomer using preparative HPLC using a column with a chiral stationary phase or resolved to produce individual enantiomers using methods known to those skilled in the art. In addition, chiral intermediates can be resolved and used to prepare individual enantiomers.

The invention also includes all isotopic variations of the compounds of the invention. An isotopic variation of the compound of the invention is defined as one in which at least one atom is replaced by an atom that has the same atomic number but has different atomic mass than the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine isotopes, such as 2H, 3H, 13C, 14C, 15N,

10 17O, 18O, 35S, 18F and 36Cl respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope is incorporated, such as 3H or 14C, are useful in studies of drug and / or substrate distribution in tissues. Particularly preferred are tritium isotopes, i.e. 3H, and carbon-14, i.e. 14C, for their ease of preparation and detectability. In addition, substitution with isotopes such as deuterium, that is, 2H, can produce certain therapeutic advantages that arise from increased metabolic stability, for example, a

15 greater half-life in vivo or reduced dosage requirements and, therefore, may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures, such as illustrative methods, or by the preparations described in the examples and in the preparations shown below using the appropriate isotopic variations of suitable reagents.

The compounds of the invention can be prepared in a variety of ways. These processes form other aspects of the invention.

Compounds of List A can be prepared as illustrated by Compound 1 below.

Compound 1 can be prepared according to scheme 1 by coupling a compound of formula (II), that is, suitable carboxylic acid, with a compound of formula (III). Typical conditions may be used that

25 comprise treatment with a suitable coupling agent, such as HATU, HOBt, DCC in a suitable solvent such as DCM or DMF. Alternative conditions include conversion of the carboxylic acid (II) into the corresponding acyl chloride, using oxalyl chloride in a suitable solvent (such as THF or DCM) with a suitable base (such as triethylamine).

Alternatively, compounds of List A can be prepared from other compounds of List A.

The Compound of formula (III) can be prepared according to scheme 2. Treatment of the compound of formula (IV) with trifluoroacetic anhydride in the presence of a base (such as triethylamine) in a suitable solvent (such as DCM) gives the compound of formula (V). Halogenation of the compound of formula (V) with a suitable radical halogen source such as sulfuryl chloride or N-bromosuccinimide in a suitable solvent

35 (such as carbon tetrachloride) gives the compound of formula (VI). Treatment of the compound of formula (VI) with a phosphine derivative (such as triphenylphosphine) gives compounds of formula (VII), which can be cyclized to give the compound of formula (VIII). Typical cycling conditions comprise heating in a suitable solvent (such as DMF) at a temperature above 100 ° C. The compound of formula (III) is obtained by reduction of the compound of formula (VIII) with nickel borane or borohydride.

Alternatively, the compounds of formula (IIIa), that is, compounds of formula (III), in which the indole nitrogen is alkylated, can be prepared according to reaction scheme 3 by reacting the compound of formula (VIII) with a suitable alkyl halide (such as methyl iodide) in the presence of a base (such as sodium hydride) in a suitable solvent (such as DMF) followed by reduction, using nickel borane or borohydride.

Salts can be prepared in a conventional manner by reaction with the appropriate acid or acid derivative.

The compounds of the invention may be useful for the treatment of diseases and conditions mediated by

10 positive allosteric modulation of nAChR a7 or diseases and conditions that are associated with modulation of nAChR a7. Diseases or conditions mediated by positive allosteric modulation of nAChR a7 or diseases and conditions that are associated with modulation of nAChR a7 include (the numbers in brackets that are after the indicated diseases refer to the classification code found in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American

15 Psychiatric Association (DSM-IV) and / or International Classification of Diseases, 10th Edition (ICD-10):

i) Psychotic disorders, for example, schizophrenia [including paranoid type subtypes (295.30), disorganized type (295.10), catatonic type (295.20), undifferentiated type (295.90) and residual type (295.60)]; schizophreniform disorder (295.40); schizoaffective disorder (295.70) [including bipolar and depressive type subtypes]; delusional disorder (297.1) [including erotomanic subtypes of

20 delirium type of greatness, celotypy, persecutory type, somatic type, mixed type and unspecified type]; brief psychotic disorder (298.8); shared psychotic disorder (297.3); psychotic disorder due to a generalized condition [including subtypes with delusions and hallucinations]; substance-induced psychotic disorder [including subtypes with delusions (293.81) and hallucinations (293.82)]; and psychotic disorder not otherwise specified (298.9).

ii) cognitive impairment including, for example, the treatment of impairment of cognitive functions that include attention disorders, orientation, learning, memory (i.e., memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and associated memory loss with age) and language function; as well as cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick's disease, AIDS-related dementia or other dementia states such as multi-infarction dementia, alcoholic dementia, hypothyroid-related dementia and dementia associated with others degenerative disorders such as cerebellar atrophy and amyotrophic lateral sclerosis; other acute or subacute conditions that can cause cognitive impairment such as delusions or depression (pseudodementia states), trauma, head trauma, age-related cognitive impairment, stroke, neurodegeneration, drug-induced states, neurotoxic agents, moderate cognitive impairment, impairment age-related cognitive impairment, cognitive impairment related to autism, Down syndrome, cognitive deficit related to other diseases such as schizophrenia, bipolar disorder, depression and other psychiatric disorders, and cognitive disorders related to post-electroconvulsive treatment; and dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias.

iii) Depression and mood disorders, for example, depressive episodes (including major depressive episode, manic episode, mixed episode and hypomanic episode); depressive disorders [including major depressive disorder, dysthymic disorder (300.4), depressive disorder not otherwise specified (311)]; bipolar disorders [including bipolar I disorder, bipolar II disorder (ie recurrent major depressive episodes with hypomanic episodes) (296.89), cyclothymic disorder (301.13) and bipolar disorder not otherwise specified (296.80)]; other disorders of emotional state [including emotional state disorder due to a generalized condition (293.83), which includes subtypes with depressive characteristics, with major depressive episode, with manic characteristics and mixed characteristics]; substance-induced emotional state disorder (which includes subtypes with depressive characteristics, with manic and mixed characteristics); and mood disorder not otherwise specified (296.90).

iv) Anxiety disorders, for example, social anxiety disorder; panic attack; agoraphobia, panic disorder; agoraphobia without a history of panic disorder (300,22); specific phobia (300.29) (including subtypes of animal type, natural environment type, blood-injection-wound type, situational type and other types); social phobia (300.23); obsessive compulsive disorder (300.3); PTSD (309.81); acute stress disorder (308.3); generalized anxiety disorder (300.02); anxiety disorder due to a generalized condition (293.84); substance induced anxiety disorder; and anxiety disorder not otherwise specified (300.00).

v) Substance-related disorders, for example, substance use disorders (including substance dependence, substance craving and substance addiction); substance-induced disorders [including substance intoxication, substance withdrawal syndrome, substance-induced delirium, substance-induced persistent dementia, substance-induced persistent amnesic disorder, substance-induced psychotic disorder, substance-induced emotional state disorder, substance-induced anxiety, substance-induced sexual dysfunction, substance-induced sleep disorder and persistent hallucination perception disorder (flashbacks); alcohol-related disorders [including alcohol dependence (303.90), alcohol addiction (305.00), alcohol intoxication (303.00), alcohol withdrawal syndrome (291.81), alcohol intoxication delirium, alcohol withdrawal syndrome delirium , alcohol-induced persistent dementia, alcohol-induced persistent amnesic disorder, alcohol-induced psychotic disorder, alcohol-induced emotional state disorder, alcohol-induced anxiety disorder, alcohol-induced sexual dysfunction, sleep disorder Alcohol-induced and alcohol-related disorder not otherwise specified (291.9)]; disorders related to amphetamines (or amphetamine substances) (for example, amphetamine dependence (304.40), amphetamine addiction (305.70), amphetamine poisoning (292.89), amphetamine withdrawal syndrome (292.0), amphetamine poisoning delirium, disorder Amphetamine-induced psychotic disorder, amphetamine-induced emotional state disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorder, and amphetamine-related disorder not otherwise specified (292.9)]; disorders related to caffeine [including caffeine poisoning (305.90), caffeine-induced anxiety disorder, caffeine-induced sleep disorder and caffeine-related disorder not otherwise specified (292.9)]; cannabis-related disorders [including cannabis dependence (304.30), cannabis addiction (305.20), poisoning with cannabis (292.89), delirium from cannabis poisoning, cannabis-induced psychotic disorder, cannabis-induced anxiety disorder and cannabis-related disorder not otherwise specified (292.9)]; Cocaine-related disorders [including cocaine dependence (304.20), cocaine addiction (305.60), cocaine intoxication (292.89), cocaine withdrawal syndrome (292.0), cocaine intoxication delirium, cocaine-induced psychotic disorder , cocaine-induced emotional state disorder, cocaine-induced anxiety disorder, cocaine-induced sexual dysfunction, cocaine-induced sleep disorder and cocaine-related disorder not otherwise specified (292.9)]; hallucinogen-related disorders [including hallucinogen dependence (304.50), hallucinogen addiction (305.30), hallucinogen poisoning (292.89), hallucinogenic persistent perception disorder (retrospective scenes) (292.89), hallucinogen poisoning delirium, induced psychotic disorder for hallucinogens, hallucinogen-induced emotional state disorder, hallucinogen-induced anxiety disorder and hallucinogen-related disorder not otherwise specified (292.9)]; inhaler-related disorders [including inhaler dependence (304.60), inhaler addiction (305.90), inhaler poisoning (292.89), delirium from inhaler poisoning, persistent inhaler-induced dementia, inhaler-induced psychotic disorder, induced emotional state disorder by inhalers, inhaler-induced anxiety disorder and inhaler-related disorder not otherwise specified (292.9)]; nicotine-related disorders [including nicotine dependence (305.1), nicotine withdrawal syndrome (292.0) and nicotine-related disorder not otherwise specified (292.9)]; opioid-related disorders [including opioid dependence (304.00), opioid addiction (305.50), opioid poisoning (292.89), opioid withdrawal syndrome (292.0), opioid intoxication delirium, opioid-induced psychotic disorder, disorder of opioid-induced emotional state, opioid-induced sexual dysfunction, opioid-induced sleep disorder and opioid-related disorder not otherwise specified (292.9)]; disorders related to phencyclidine (or substances of the phencyclidine type) [including dependence on phencyclidine (304.60), addiction to phencyclidine (305.90), poisoning with phencyclidine (292.89), delirium caused by phencyclidine poisoning, psychotic disorder induced by fenciclidine , Phencyclidine-induced emotional state disorder, Phencyclidine-induced anxiety disorder and Phencyclidine-related disorder not otherwise specified (292.9)]; sedative, hypnotic or anxiolytic-related disorders [including sedative, hypnotic or anxiolytic dependence (304.10), sedative, hypnotic or anxiolytic addiction (305.40), sedative, hypnotic or anxiolytic poisoning (292.89), sedative withdrawal, hypnotic syndrome or anxiolytic (292.0), delirium from sedative, hypnotic or anxiolytic intoxication, delirium from sedative, hypnotic or anxiolytic withdrawal, persistent sedative, hypnotic or anxiolytic dementia, persistent sedative, hypnotic amnesic disorder

or anxiolytics, sedative, hypnotic or anxiolytic induced psychotic disorder, sedative, hypnotic or anxiolytic induced emotional state disorder, sedative, hypnotic or anxiolytic induced anxiety disorder, sedative, hypnotic or anxiolytic induced sexual dysfunction, sleep induced disorder for sedatives, hypnotics or anxiolytics and sedative, hypnotic or anxiolytic-related disorder not otherwise specified (292.9)]; disorder related to many substances [including dependence on many substances (304.80)]; and disorders related to other substances (or unknown substances) [including anabolic steroids, nitrate inhalers and nitrous oxide].

vi) Sleep disorders, for example, primary sleep disorders such as dysomnia (including primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), sleep disorders related to breathing (780.59), circadian rhythm disorders of sleep (307.45) and dysomnia not otherwise specified (307.47)); primary sleep disorders such as, for example, parasomnios [including nightmare disorder (307.47), sleep terror disorder (307.46), sleepwalking disorder (307.46) and parasomnios not otherwise specified (307.47)]; sleep disorders related to another mental disorder [including insomnia related to another mental disorder (307.42) and hypersomnia related to another mental disorder (307.44)]; sleep disorder due to a generalized condition; and substance-induced sleep disorder (including insomnia, hypersomnia, parasomnia and mixed type subtypes).

vii) Eating disorders such as anorexia nervosa (307.1) (including restrictive and bulimic type subtypes); bulimia nervosa (307.51) (including subtypes of type with vomit and type without vomit); obesity; binge eating disorder; Binge eating disorder; and eating disorder not otherwise specified (307.50).

viii) Autism spectrum disorders including autistic disorder (299.00), Asperger disorder, Rett disorder, childhood disintegrative disorder and generalized developmental disorder not otherwise specified.

ix) Hyperactivity disorder / attention deficit (including subtypes of hyperactivity disorder / attention deficit of the combined type (314.01), hyperactivity disorder / attention deficit predominantly inattentive type (314.00), hyperactivity disorder / attention deficit hyperactive-impulsive type (314.01) and hyperactivity disorder / attention deficit not otherwise specified (314.9)); hyperkinetic disorder; destructive behavior disorders such as behavioral disorders [including subtypes of the type of onset in childhood (321.81), of the type of onset in adolescence (312.82) and of unspecified onset (312.89), provocative disorder with resistance

(313.81) and destructive behavior disorder not otherwise specified]; and tics disorders such as Tourette's disorder (307.23).

x) Personality disorders including subtypes paranoid personality disorder (301.0), schizoid personality disorder (301.20), schizotypal personality disorder (301.22), antisocial personality disorder (301.7), borderline personality disorder (borderline) (301.83), histrionic personality disorder (301.50), narcissistic personality disorder (301.81), avoidance personality disorder (301.82), dependent personality disorder (301.6), obsessive personality disorder- compulsive (301.4) and personality disorder not otherwise specified (301.9).

xi) Sexual dysfunctions such as sexual desire disorders [including hypoactive sexual desire disorder (302.71) and sexual aversion disorder (302.79)]; sexual arousal disorders [including female sexual arousal disorder (302.72) and male erectile disorder (302.72)]; orgasm disorders (including female orgasm disorder (302.73), male orgasm disorder (302.74) and premature ejaculation (302.75)); sexual pain disorder (including dyspareunia (302.76) and vaginismus (306.51)); sexual dysfunction not otherwise specified (302.70); paraphilias (including exhibitionism (302.4), fetishism (302.81), rubbing (302.89), pedophilia (302.2), sexual masochism (302.83), sexual sadism (302.84), tragic fetishism (302.3), voyeurism (302.82) and unspecified paraphilias of other way (302.9)); sexual identity disorders (including sexual identity disorder in children

(302.6) and sexual identity disorder in adolescents or adults (302.85)); and sexual disorder not otherwise specified (302.9).

The compounds of the invention are also useful in the treatment of inflammation, inflammatory pain, rheumatoid arthritis and sepsis.

In one embodiment, the patient is a human being. The term "treatment" includes prophylaxis, when it is appropriate for the relevant condition or conditions.

Therefore, in one aspect, the present invention provides a compound of List A as described hereinbefore or a salt thereof for use as a medicament.

In another aspect, the present invention provides a compound of List A as described hereinbefore or a salt thereof for use in the treatment of a disease, which is associated with a reduction in the function of the nicotinic receptor of acetylcholine a7.

In another aspect, the present invention provides a List A compound as described hereinbefore or a salt thereof for use in the treatment of a disease that benefits from a positive allosteric modulation of the nicotinic acetylcholine a7 receptor. .

In another aspect, the present invention provides a compound of List A as described hereinbefore or a salt thereof for use as a positive allortic modulator of the nicotinic acetylcholine a7 receptor.

In another aspect, the invention provides a compound of List A as described hereinbefore or a salt thereof for use in the treatment of a psychotic disorder. In one embodiment, the invention provides a compound of List A as described hereinbefore or a salt thereof for use in the treatment of schizophrenia. In one embodiment, the invention provides a compound of List A as described hereinbefore or a salt thereof for use in the treatment of anxiety or depression.

The invention also provides a List A compound as described hereinbefore or a salt thereof for use in the treatment of cognitive impairment.

The invention also provides a compound of List A as described hereinbefore or a salt thereof for use in the treatment of Alzheimer's disease.

In another aspect, the invention provides the use of a List A compound as described hereinbefore or a salt thereof in the manufacture of a medicament for treating a disease that is associated with a reduction in the function of the nicotinic acetylcholine a7 receptor.

In another aspect, the invention provides the use of a List A compound as described hereinbefore or a salt thereof in the manufacture of a medicament for use in the treatment of a disease that benefits from modulation. Allosteric positive nicotinic acetylcholine receptor a7.

In another aspect, the invention provides the use of a compound of List A as described hereinbefore or a salt thereof in the manufacture of a medicament for positive allosteric modulation of the nicotinic acetylcholine a7 receptor.

In another aspect, the invention provides the use of a List A compound as described hereinbefore or a salt thereof in the manufacture of a medicament for use in the treatment of a psychotic disorder.

In another aspect, the invention provides the use of a List A compound as described hereinbefore or a salt thereof in the manufacture of a medicament for use in the treatment of schizophrenia.

In another aspect, the invention provides the use of a compound of List A as described hereinbefore or a salt thereof in the manufacture of a medicament for use in the treatment of anxiety or depression.

In another aspect, the invention provides the use of a List A compound as described hereinbefore or a salt thereof in the manufacture of a medicament for use in the treatment of cognitive impairment.

In another aspect, the invention provides the use of a List A compound as described hereinbefore or a salt thereof in the manufacture of a medicament for use in the treatment of Alzheimer's disease.

In another aspect, the invention describes a method for treating a disease that is associated with a reduction in the function of the nicotinic acetylcholine a7 receptor, which comprises administering to a human being in need thereof an effective amount of a List A compound as described herein or a salt thereof.

In one aspect, the present invention describes a method of treating a disease that benefits from the positive allosteric modulation of the nicotinic acetylcholine a7 receptor, which comprises administering to a human being in need thereof an effective amount of a List A compound as described herein or a salt thereof.

In one aspect, the present invention describes a method for positive allosteric modulation of the nicotinic acetylcholine a7 receptor, which comprises administering to an human being an effective amount of a compound of List A as described hereinbefore or a Get out of it.

In another aspect, the invention describes a method for use in the treatment of a psychotic disorder, which comprises administering to an human being in need thereof an effective amount of a compound of List A as described hereinbefore or a Get out of it.

In one embodiment, the invention describes a method for treating schizophrenia, which comprises administering to an human being in need thereof an effective amount of a compound of List A as described hereinbefore or a salt thereof.

In one embodiment, the invention describes a method of treating anxiety or depression, which comprises administering to an human being in need thereof an effective amount of a compound of List A as described hereinbefore or a salt of the same.

The invention also describes a method for treating cognitive impairment, which comprises administering to an human being in need thereof an effective amount of a compound of List A as described hereinbefore or a salt thereof.

The invention also describes a method for treating Alzheimer's disease, which comprises administering to an human being in need thereof an effective amount of a compound of List A as described hereinbefore or a salt thereof.

In general, the compounds in List A or a salt thereof can be administered in doses ranging from about 0.1 mg to about 1000 mg per day, in individual or divided doses (i.e., 1 to 4 doses per day). ), although variations will necessarily be made depending on the species, weight, age and condition of the subject in question, as well as the particular route of administration chosen. In one embodiment, the dose is administered once a day. In one embodiment, the dosage level is in the range of about 0.1 mg / kg to about 500 mg / kg of body weight per day. In a further embodiment, the dosage level is in the range of about 0.1 mg / kg to about 100 mg / kg of body weight per day.

The compounds of List A and their salts may also be suitable to be combined with other active ingredients, such as typical and atypical antipsychotics, mood stabilizers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and cognitive enhancers, to provide better Treatment of psychotic disorders.

The combination therapies of the invention, for example, are coadjuvantly administered. By adjuvant administration is meant the overlapping or coincidental administration of each of the components as pharmaceutical compositions or separate devices. This therapeutic administration regimen of two or more therapeutic agents is generally referred to by those skilled in the art and herein as adjuvant therapeutic administration; It is also known as additive therapeutic administration. Within the scope of the present invention are each and every treatment regimen in which a patient receives separate but overlapping or overlapping therapeutic administration of List A compounds.

or a salt thereof and at least one antipsychotic agent, a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects or a cognitive enhancer. In an embodiment of adjuvant therapeutic administration as described herein, a patient typically stabilizes with the therapeutic administration of one or more of the components over a period of time and then receives administration of another component. The compounds of List A or a salt thereof may be administered as adjunctive therapeutic treatment to patients who are receiving the administration of at least one antipsychotic agent, a mood stabilizer, an antidepressant, an anxiolytic agent, a drug for side effects. extrapyramidal or a cognitive enhancer, but the scope of the invention also includes the adjuvant therapeutic administration of at least one antipsychotic agent, a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects or a cognitive enhancer to patients who are receiving the administration of compounds of List A or a salt thereof.

The combination therapies of the invention can also be administered simultaneously. Simultaneous administration means a treatment regimen in which the individual components are administered together, in the form of a single pharmaceutical composition or device comprising or containing the two components, or as separate compositions or devices, each comprising one of the components, administered simultaneously. These combinations of the separate individual components for simultaneous combination can be provided in the form of a kit of parts.

In a further aspect, the invention describes a method of treating a psychotic disorder by means of the adjuvant therapeutic administration of List A compounds or a salt thereof to a patient receiving the therapeutic administration of at least one antipsychotic agent. In a further aspect, the invention provides the use of List A compounds or a salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of at least An antipsychotic agent. The invention also provides compounds of List A or a salt thereof for use for adjuvant therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of at least one antipsychotic agent.

In a further aspect, the invention describes a method of treating a psychotic disorder by means of the adjuvant therapeutic administration of at least one antipsychotic agent to a patient receiving the therapeutic administration of List A compounds or a salt thereof. In a further aspect, the invention provides the use of at least one antipsychotic agent in the manufacture of a medicament for adjuvant therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of List A compounds or a Get out of them. The invention also provides at least one antipsychotic agent for adjuvant therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of List A compounds or a salt thereof.

In a further aspect, the invention describes a method for the treatment of a psychotic disorder by the simultaneous therapeutic administration of List A compounds or a salt thereof in combination with at least one antipsychotic agent. The invention also provides the use of a combination of List A compounds or a salt thereof and at least one antipsychotic agent in the preparation of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention also provides the use of List A compounds or a salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention additionally provides List A compounds or a salt thereof for use for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention also provides the use of at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration with List A compounds or a salt thereof in the treatment of a psychotic disorder.

In a further aspect, the invention provides a kit of parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising compounds of List A or a salt thereof and one or more additional dosage forms that they comprise, each, an antipsychotic agent for simultaneous therapeutic administration.

In another aspect, the invention describes a method of treating a psychotic disorder by means of the adjuvant therapeutic administration of a compound of the present invention to a patient receiving a therapeutic administration of an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer.

In a further aspect, the invention provides the use of a compound of the present invention in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of an active ingredient selected from the group. which consists of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer.

The invention also provides the use of a compound of the present invention in the adjuvant therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of an active ingredient selected from the group consisting of: a stabilizer of the state of Mood, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer.

The invention further provides the use of a compound of the present invention for use for adjuvant therapeutic administration for the treatment of a psychotic disorder in a patient receiving the therapeutic administration of an active ingredient selected from the group consisting of: a stabilizer of the mood, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer.

In a further aspect, the invention describes a method of treating a psychotic disorder by means of the adjuvant therapeutic administration of an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer to a patient receiving therapeutic administration of a compound of the present invention.

In a further aspect, the invention provides the use of an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer in the preparation of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of a compound of the present invention.

The invention also provides the use of an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of a compound of the present invention.

In a further aspect, the invention describes a method of treating a psychotic disorder by means of the simultaneous therapeutic administration of a compound of the present invention together with an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer.

The invention also provides the use of a combination of a compound of the present invention and an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and an enhancer cognitive in the preparation of a medication for simultaneous therapeutic administration in the treatment of a psychotic disorder.

The invention also provides the use of a combination of a compound of the present invention and an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and an enhancer Cognitive for simultaneous therapeutic administration in the treatment of a psychotic disorder.

The invention also provides the use of a compound of the present invention in the manufacture of a medicament for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer in the treatment of a psychotic disorder.

The invention further describes the use of a compound of the present invention for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer in the treatment of a psychotic disorder.

The invention also provides a compound of the present invention for use for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and an enhancer Cognitive in the treatment of a psychotic disorder.

The invention further provides the use of an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer in the preparation of a medicament for therapeutic administration. simultaneous with a compound of the present invention in the treatment of a psychotic disorder.

The invention further provides the use of an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer for simultaneous therapeutic administration with a compound of the present invention in the treatment of a psychotic disorder.

In a further aspect, the invention provides a kit of parts for use in the treatment of a psychotic disorder, which comprises a first dosage form comprising a compound of the present invention and one or more additional dosage forms comprising, each , an active ingredient selected from the group consisting of: a mood stabilizer, an antidepressant, an anxiolytic, a drug for extrapyramidal side effects and a cognitive enhancer for simultaneous therapeutic administration.

Examples of antipsychotic drugs that may be useful in the present invention include, but are not limited to: sodium channel blockers; mixed 5HT antagonists / dopamine receptor; mGluR5 positive modulators; D3 antagonists; 5HT6 antagonists; alpha-7 nicotinic receptor modulators; GlyT1 glycine transporter inhibitors; partial D2 agonists / D3 antagonists / H3 antagonists; AMPA modulators; NK3 antagonists such as osanetant and talnetant; an atypical antipsychotic, for example clozapine, olanzapine, risperidone, quetiapine, aripyrazole, ziprasidone and amisulpride; butyrophenones, such as haloperidol, pimozide and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, tiflupromazine, prochlorperazine and acetophenazine; thioxanthenes, such as thiothixen and chlorprothixen; thienobenzodiazepines; dibenzodiazepines; benzoisoxazoles; dibenzothiazepines; imidazolidinones; benzoisothiazolylpiperazines; triazine such as lamotrigine; dibenzoxacepins, such as loxapine; dihydroindolones, such as molindone; aripiprazole; and derivatives thereof that have antipsychotic activity.

Examples of trade names and suppliers of selected antipsychotic drugs that may be suitable for use in the present invention are: clozapine (available under the trade name CLOZARIL ™, from Milan, Zenit Goldline, UDL, Novartis); olanzapine (available under the trade name ZYPREXA ™, from Lilly; ziprasidone (available under the trade name GEODON ™, from Pfizer); risperidone (available under the trade name RISPERDAL ™, from Janssen); quetiapine fumarate (available under the trade name SEROQUEL ™, from AstraZeneca); sertindole (available under the trade name SERLECT ™); amisulpride (available under the trade name SOLION ™, from Sanofi-Synthelabo); haloperidol (available under the trade name HALDOL ™, from Orto-McNeilo); haloperidol decanoate (available under the trade name HALDOL decanoate ™; haloperidol lactate (available under the trade names HALDOL ™ and INTENSOL ™); chlorpromazine (available under the trade name THORAZINE ™, from SmitKline Beecham (GSK); fluphenazine (available with the trade name PROLIXIN ™, from Apotecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); fluphenazine decanoate (available under the trade name PROLIXI N decanoate ™); fluphenazine enanthate (available under the trade name PROLIXIN ™); fluphenazine hydrochloride (available under the trade name PROLIXIN ™); thiothixen (available under the trade name NAVANE ™; from Pfizer); thiothixen hydrochloride (available under the trade name NAVANE ™); trifluoperazine (10- [3- (4-methyl-1-piperazinyl) propyl] -2- (trifluoromethyl) phenothiazine dihydrochloride, available under the trade name STELAZINE ™, from SmithKline Beckman; perphenazine (available under the trade name TRILAFON ™; from Schering ); perfenazine and amitriptyline hydrochloride (available under the trade name ETRAFON TRILAFON ™); thioridazine (available under the trade name MELLARIL ™; from Novartis, Roxane, hiTech, Teva, and Alfarma); molindone (available under the trade name MOBAN ™ , from Endo); molindone hydrochloride (available under the trade name MOBAN ™); loxapine (available under the trade name LOXITANE ™; from Watson); loxapine hydrochloride (available under the trade name LOXITANE ™); and loxapine succinate ( available under the trade name LOXITANE ™) In addition, benperidol (Glianimon ™), perazine (Taxilan ™) or melperone (Eunerpan ™) can be used.

Other suitable antipsychotic drugs include promazine (available under the trade name SPARINE ™), triflurpromazine (available under the trade name VESPRIN ™), chlorprotixen (available under the trade name TARACTAN ™), droperidol (available under the trade name INAPSINE ™), acetophenazine (available under the trade name TINDAL ™), prochlorperazine (available under the trade name COMPAZINE ™), metotrimeprazine (available under the trade name NOZINAN ™), pipothiazine (available under the trade name PIPOTRIL ™), iloperidone, pimozide and flupentixol.

Antipsychotic drugs indicated above by the trade name may also be available from other providers with a different trade name.

In a further aspect of the invention, suitable antipsychotic agents include olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone, talnetant and osanetant.

Mood stabilizers that can be used in the therapy of the present invention include lithium, sodium valproate / valproic acid / divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, oxcarbazepine and thiagabine.

Antidepressant drugs that can be used in the therapy of the present invention include serotonin antagonists, CRF-1 antagonists, dual Cox-2 / SSRI inhibitors; triple dopamine / noradrenaline / serotonin reuptake inhibitors; NK1 antagonists; dual antagonists of NK1 and NK2; dual NK1 / SSRI antagonists; NK2 antagonists; serotonin agonists (such as rauwolscin, yohimbine and metoclopramide); serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, fluvoxamine, femoxetine, indalpine, zimeldine, paroxetine and sertraline); dual serotonin / noradrenaline reuptake inhibitors (such as venlafaxine, reboxetine, duloxetine and milnacipran); norepinephrine reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); 5HT3 antagonists (such as, for example, ondansetron and granisetron); and others (such as bupropion, aminaptin, radafaxine, mianserin, mirtazapine, nefazodone and trazodone).

Anxiolytics that can be used in the therapy of the present invention include V1b antagonists, 5HT7 antagonists and benzodiazepines such as alprazolam and lorazepam.

The drugs for extrapyramidal side effects that can be used in the therapy of the present invention include anticholinergics (such as benztropine, biperiden, procyclylidine and trihexyphenyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine).

Cognitive enhancers that can be used in the therapy of the present invention include, for example, cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine), H3 antagonists and M1 muscarinic agonists (such as cevimeline).

In one embodiment, the active ingredient for use together with a compound of the present invention is an atypical antipsychotic, for example clozapine, olanzapine, risperidone, quetiapine, aripyrazole, ziprasidone or amisulpride.

In one embodiment, the active ingredient for use in conjunction with a compound of the present invention is a typical antipsychotic, for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perfenazine, prochlorperazine, trifluoperazine, thiothixin, haloperidol, tiflurpromazine, pimozide, droperidol, chlorperidol molindone or loxapine.

In another embodiment, the active ingredient for use together with a compound of the present invention is a mood stabilizer, for example lithium, sodium valproate / valproic acid / divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, oxcarbazepine or thiagabine.

In another embodiment, the active ingredient for use in conjunction with a compound of the present invention is an antidepressant, for example a serotonin agonist (such as rauwolscin, yohimbine or metoclopramide); a serotonin reuptake inhibitor (such as citalopram, escitalopram, fluoxetine, fluvoxamine, femoxetine, indalpine, zimeldine, paroxetine or sertraline); a dual serotonin / noradrenaline reuptake inhibitor (such as venlafaxine, reboxetine, duloxetine or milnacipran); a norepinephrine reuptake inhibitor (such as reboxetine); a tricyclic antidepressant (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline or trimipramine); a monoamine oxidase inhibitor (such as isocarboxazide, moclobemide, phenelzine or tranylcypromine); or others (such as bupropion, aminaptin, radafaxine, mianserin, mirtazapine, nefazodone or trazodone).

In another embodiment, the active ingredient for use together with a compound of the present invention is an anxiolytic, for example a benzodiazepine such as alprazolam or lorazepam.

For use in medicine, the compounds of the present invention are usually administered in the form of a normal pharmaceutical composition. Therefore, the present invention, in a further aspect, provides a pharmaceutical composition comprising a compound of List A as described hereinbefore or a salt thereof and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition can be used in the treatment of any of the ailments described herein.

The compounds of the invention can be administered by any convenient method, for example by oral, parenteral (for example, intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions can be adapted accordingly. The compounds of the invention that are active when administered orally can be formulated as liquids or solids, for example, syrups, suspensions or emulsions, tablets, capsules and dragees.

A liquid formulation, in general, will consist of a suspension or solution of the compound or salt in a suitable liquid vehicle or vehicles, for example, an aqueous solvent such as water, ethanol or glycerin, or a non-aqueous solvent, such as polyethylene glycol or a oil. The formulation may also contain a suspending, preservative, flavoring or coloring agent.

A tablet-shaped composition can be prepared using any pharmaceutically acceptable carrier or vehicles commonly used to prepare solid formulations. Examples of such vehicles include magnesium stearate, starch, lactose, sucrose and cellulose.

A capsule-shaped composition can be prepared using standard encapsulation procedures. For example, granules containing the active ingredient can be prepared using standard carriers and then loaded into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any pharmaceutically acceptable carrier or vehicles, for example, aqueous gums, celluloses, silicates, or oils, and then loading the dispersion or suspension into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous vehicle or parenterally acceptable oil, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just before administration.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent, and are usually presented in amounts of a single dose or multiple doses in sterile form in a closed container, which can be shaped. of a cartridge or refill for use with an atomization device. Alternatively, the closed container may be a unit dispensing device such as a single dose nasal inhaler or an aerosol dispenser equipped with a metering valve that is intended to be discarded once the contents of the package have been finished. When the dosage form comprises an aerosol dispenser, it will contain a propellant that can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage forms can also be in the form of a pump atomizer.

Compositions suitable for oral and sublingual administration include tablets, dragees and tablets, in which the active ingredient is formulated with a vehicle such as sugar and gum arabic, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches. The composition may be in a unit dose form such as a tablet, capsule or blister.

The composition may be in a unit dose form such as a tablet, capsule or blister. Each dosage unit for oral administration may contain, for example, from 1 to 500 mg (and for parenteral administration it contains, for example, 0.1 to 50 mg) of a compound of the formula (I) or a salt thereof calculated as the free base. In one embodiment, the unit dose for oral administration contains 50 to 450 mg. In a further embodiment, the unit dose contains 100 to 400 mg.

In order to achieve consistency of adjuvant administration, the compositions of each of the components

or of the combination of the components is, for example, in the form of a unit dose.

Support compounds

The preparation of various compounds of the invention is described below.

In the procedures shown below, after each starting material, a reference to the intermediate is typically provided. This is provided merely as an aid to the specialist chemist. The starting material may not necessarily have been prepared from the indicated batch. The compounds and intermediates of the invention are named using the chemical nomenclature software ACD / Name PRO

6.02 (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).

Abbreviations

TORCH

Triethylamine

TFA

Trifluoroacetic acid

TFAA

Trifluoroacetic acid anhydride

DAD

Diode Series Detector

LC / MS

Liquid chromatography / mass spectrometry

NMR

Nuclear magnetic resonance

THF

Tetrahydrofuran

DMSO

Dimethylsulfoxide

DMF

Dimethylformamide

DCM / MDC

Dichloromethane / Methylene Dichloride

CDI

1,1'-Carbonyldiimidazole

EDC

1-Ethyl-3- (dimethylaminopropyl) carbodiimide

HOAt

1-Hydroxy-7-azabenzotriazole

HOBt

1-Hydroxybenzotriazole

Pd over C

Palladium on carbon

MeCN

Acetonitrile

MDAP

Mass-directed self-preparation

Cy

 Cyclohexane

EtOAc

Ethyl acetate

IS -

Electrospray

ES-API

Electrospray - atmospheric pressure ionization

min

Minutes

I

Methyl

Et

Ethyl

ºC

Degrees Celsius

SCX

Strong cation exchange

SAX

Strong anion exchange

h

Hours)

DIPEA

N, N-Diisopropylethylamine

HEY YOU

O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate

NBS

N-Bromosuccinimide

The starting materials were obtained from commercial suppliers and were used without further purification, unless otherwise indicated. Flash chromatography was performed using prepackaged Isolute Flash ™ or Biotage ™ silica gel columns as stationary phase and analytical grade solvents as eluent, unless otherwise indicated.

NMR spectra were obtained at 298K, 303.2K or 300K, at the frequency set using a Bruker ™ DPX400 or AV400 machine and performed as a dilute solution of CDCl3, unless otherwise indicated. All NMR spectra made reference to tetramethylsilane (TMS oH 0, oc 0). All coupling constants are indicated in hertz (Hz), and multiplicities are marked as s (singlet), sa, (wide singlet), d (doublet), t (triplet), c (quadruplet), dd (doublet of doublets), dt (triplet doublet) and m (multiplet).

One of the following methods was used for the LC / MS analysis:

Method 1

Column: Waters Atlantis, 4.6 mm x 50 mm. The particle size of the stationary phase is 3 µm.

Solvents: A: Aqueous solvent = Water + 0.05% formic acid;

B: Organic solvent = acetonitrile + 0.05% formic acid Method: 5 minutes of runtime.

Time / min

% of B Time (min) % of B

0

3  0 3

0.1

3  0.1 3

4

97 4.2 100

4.8

97  4.8 100

4.9

3  4.9 3

5.0

3  5.0 3

Flow rate: 3 ml / min

5 Injection volume: 5µl

Column temperature: 30 ºC

UV wavelength range: 220-330 nm

Method 2

Column: Waters Acquity BEH UPLC C18, 2.1 mm x 50 mm. The particle size of the stationary phase is

10 1.7 µm. Solvents

A: Aqueous solvent = Water + 0.05% formic acid

B: Organic solvent = acetonitrile + 0.05% formic acid Weak wash = Methanol: 1: 1 water

15 Strong wash = Water The generic method used has a run time of 2 minutes.

Time / min

% of B Time (min) % of B

0

3  0 3

0.1

3 1.5 100

1.5

97 1.9 100

1.9

97 2.0 3

2.0

3

•

The above method has a flow rate of 1 ml / min.

•

The injection volume for the generic method is 0.5 µl.

•

The temperature of the column is 40 degrees.

•

The UV detection range is 20 to 330 nm.

Total ionic current graphs were obtained for positive and negative electrospray ionization (ES + / ES-) 16

and / or positive and negative chemical ionization at atmospheric pressure (AP + / AP-).

All retention times cited were measured using LC / MS (Liquid Chromatography / Mass Spectrometry). When appropriate, these retention times were used as a guideline for purification using mass directed self-purification (MDAP).

Purification

Several of the compounds were purified using HPLC techniques incorporating a Mass Directed Self-Purification System (MDAP) and an appropriate mass spectrometer, such as the Waters® ZQ mass spectrometer.

Intermediate 1: N- (4-Cyano-2-methylphenyl) -2,2,2-trifluoroacetamide

In a round bottom flask, 4-amino-3-methylbenzonitrile (Alfa Aesar, Avocado Lancaster; 10.88 g, 82 mmol) and Et3N (22.95 ml, 165 mmol) in DCM (200 ml) were stirred at 0 ° C . TFAA (13.95 ml, 99 mmol) was added slowly by means of an addition funnel and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into 2M HCl (150 ml). Then, the organic layer was collected and then washed with a saturated solution of

Sodium bicarbonate (150 ml), dried (MgSO4), filtered and the solvent removed to give a dark yellow solid (19.37 g);

m / z (ES-) 227 (M-1); 1H NMR (400 MHz, CDCl3): or 8.43 (1H, d), 7.91 (1H, sa), 7.59 (1H, dd), 7.56 (1H, s), 2.37 ( 3H, s).

Intermediate 2: ({5-Cyano-2 - [(trifluoroacetyl) amino] phenyl} methyl) (triphenyl) phosphonium chloride

N- (4-cyano-2-methylphenyl) -2,2,2-trifluoroacetamide (Intermediate 1, 19.37 g, 85 mmol), sulfuryl dichloride (27.6 ml, 340) were heated in a round bottom flask mmol) and diphenylperoxyanhydride (1,028 g, 4.24 mmol) in carbon tetrachloride (210 ml) at 100 ° C for 3 h. The mixture was cooled to room temperature and then, the reaction mixture was poured into 2M HCl (350 ml). Then, the organic layer was collected and the solvent was removed to give N- [2

25 (chloromethyl) -4-cyanophenyl] -2,2,2-trifluoroacetamide in the form of an orange oil, (25.54 g) which was used in the next step without further purification. This oil was added to triphenylphosphine (26.2 g, 100 mmol) and the mixture was heated in toluene (300 ml) at 110 ° C for 3 h. The mixture was cooled to room temperature overnight and the precipitate was filtered and washed with small amounts of toluene and diethyl ether to give the title compound as an off-white solid (29.91 g);

30 m / z (ES +) 489; 1H NMR (400 MHz, CDCl3): or 12.32 (1H, s), 7.79-7.57 (16H, m), 7.50 (1H, d), 7.38 (1H, s), 6.18 (2H, d).

Intermediate 3: 2-Trifluoromethyl-1H-indole-5-carbonitrile

({5-Cyano-2 - [(trifluoroacetyl) amino] phenyl} methyl) (triphenyl) phosphonium chloride (Intermediate 2, 50.41 g, 95 mmol) in DMF (180 ml) was heated at 140 ° C for 7 h. The mixture was cooled to room temperature and the solvents evaporated. This residue was combined with the corresponding residue from another experiment (in which Intermediate 2, 7.9 g, 15.05

mmol was heated in DMF (50 ml) at 155 ° C for 2 h). The combined residues were azeotropically distilled with toluene (100 ml x 2). The resulting residue was treated with diethyl ether (500 ml) and the precipitate was filtered and washed with diethyl ether (100 ml). The filtrate was evaporated and the resulting orange oil (~ 60 g) was dissolved in DCM (200 ml) and stirred at room temperature. Iso-hexane was added until the turbidity was maintained (~ 400 ml) and the mixture was stirred for 3 days. No precipitate was observed, whereby the mixture was evaporated and chromatographed (Biotage 75L, eluting with dichloromethane) to give the title compound as a colorless solid (21.7 g);

m / z (ES-) 209 (M-1); 1H NMR (400 MHz, CDCl3): 8.85 (1H, sa), 8.08 (1H, s), 7.57 (1H, d), 7.53 (1H, d), 7.03 (1H , s).

Intermediate 4: [(2-Trifluoromethyl-1H-indol-5-yl) methyl] amine

A solution of 2-trifluoromethyl-1H-indole-5-carbonitrile (Intermediate 3, 0.16 g, 0.771 mmol) in tetrahydrofuran (5 ml), cooled in an ice-water bath, was treated dropwise with a solution 1 M of borane tetrahydrofuran complex (3.05 ml, 3.05 mmol) by syringe. Then, the reaction mixture was allowed to stir under an argon atmosphere for 18 h while allowing to warm to room temperature. Then, the reaction mixture is

It was quenched with methanol (10 ml) and stirred at room temperature for 10 min. Then, the reaction mixture was poured into an SCX cartridge (10 g) and washed well with methanol. Then, the desired product was eluted using a 2M solution of ammonia / methanol. Evaporation to dryness gave the title compound that was used in the next step without further purification.

Intermediate 5: [(2-Trifluoromethyl-1H-indol-5-yl) methyl] amine hydrochloride

A solution of 2- (trifluoromethyl) -1H-indole-5-carbonitrile (Intermediate 3, 21.7 g, 103 mmol) in THF (300 ml), cooled in an ice-water bath, was treated with borane complex and tetrahydrofuran (250 ml, 250 mmol) added dropwise by means of an addition funnel. The mixture was stirred under an argon atmosphere for 5 h while allowing to warm to room temperature. Then, the mixture was stirred for a further 18 h at room temperature. Methanol (100 ml) was added dropwise and then the mixture was stirred for 20 min at room temperature. The solvents were removed and the residue was dissolved in methanol (300 ml). Then, the mixture was heated at reflux for 1 h. The mixture was cooled to room temperature, HCl / ether (1 M, 200 ml) was added and the solvents evaporated. The residue was triturated with diethyl ether (2 x 200 ml). The residue was suspended in DCM (50 ml) and diethyl ether (300 ml) and an additional portion of HCl in ether (1 M, 100 ml) was added. Then, the mixture was filtered under an atmosphere of Ar and the

The solid was dried in a vacuum oven to give the title compound as a colorless solid (21.7 g);

m / z (ES-) 213 (M-1); 1H NMR (400 MHz, d6 DMSO): or 12.45 (1H, sa), 8.35 (3H, sa), 7.79 (1H, s), 7.53 (1H, d), 7.42 (1H, dd), 7.08 (1H, s), 4.09 (2H, c).

Intermediate 6: 6- [3- (ethyloxy) phenyl] -3-pyridinecarboxylic acid

To a solution of 6-bromo-3-pyridinecarboxylic acid (Sigma-Aldrich; 100 mg, 0.495 mmol) in 1,2-dimethoxyethane (9 ml) was added [3- (ethyloxy) phenyl] boronic acid (Sigma- Aldrich; 247 mg, 1,485 mmol), sodium carbonate (315 mg, 2.97 mmol) pre-dissolved in water (1 ml) and bis (triphenylphosphine) palladium (II) chloride (52.1 mg, 0.074 mmol). The mixture was heated at 140 ° C for 30 min in a microwave reactor (high absorbance). Ethyl acetate and water were added, followed by aqueous HCl (5 M). The aqueous phase was extracted with more amount of ethyl acetate. Phases

Organic was evaporated to dryness and purified using a 5 g SAX column that was preconditioned with MeOH. The column was washed with MeOH (2 column volumes) and then eluted with 0.5 M NH3 / MeOH. The eluent was evaporated to dryness under reduced pressure to give a yellow solid. Purification by MDAP gave the title compound as a white solid (29 mg);

m / z [M + H] + 244 (M + 1); 1H-NMR (400 MHz, MeOD): or 9.17 (1H, m), 8.39-8.42 (1H, m), 7.96-7.98 (1H, m), 7.57- 7.62 (2H, m), 7.38-7.42 (1H, m), 7.02-7.05 (1H, m), 4.14 (2H, c), 1.42 (3H, t).

Intermediate Product 7: 2- [3- (ethyloxy) phenyl] -5-pyrimidinecarboxylic acid

To a solution of 2-chloro-5-pyrimidinecarboxylic acid (Anichem LLC; 100 mg, 0.631 mmol) in 1,2-dimethoxyethane (9 ml) was added [3- (ethyloxy) phenyl] boronic acid (Sigma-Aldrich; 314 mg, 1,892 mmol), sodium carbonate (401 mg, 3.78 mmol) pre-dissolved in water (1 ml) and bis (triphenylphosphine) palladium (II) chloride (66.4 mg, 0.095 mmol). The mixture was heated at 140 ° C for 30 minutes in a microwave reactor (high absorbance). The catalyst was filtered and the liquor

10 mother evaporated to dryness. Purification using MDAP gave the title compound as a white solid (10 mg);

m / z [M + H] + 245 (M + 1); 1H-NMR (400 MHz, MeOD): or 9.29 (assumed 1H, s), 8.03-8.08 (2H, m), 7.61-7.70 (1H, m), 7.50 -7.60 (1H, m), 7.39-7.42 (1H, m), 7.08-7.11 (1H, m), 4.10-4.16 (2H, c), 1 , 43 (3H, t).

Intermediate 8: 5-Chloro-2-pyrazinecarboxylic acid

A solution of methyl 5-chloro-2-pyrazinecarboxylate (Bio-Farma; 1.50g, 8.69 mmol) in a mixture of methanol (16 ml) and water (8 ml) was stirred at room temperature and treated with potassium carbonate (1.201 g, 8.69 mmol). The resulting solution was stirred for 2 h and the methanol was removed under reduced pressure. The residue was partitioned between ethyl acetate and water (20 ml) and the aqueous phase was acidified by the addition of 5 M hydrochloric acid. Extraction (x 2)

20 with ethyl acetate and drying over MgSO4, followed by removal of the solvent under reduced pressure, gave the title compound (1.00 g) as a white solid;

m / z (ES-) 157 (M-H); 1 H NMR (400 MHz, CDCl 3) 9.22 (1 H, s), 8.69 (1 H, s) ppm.

Intermediate Product 9: 6- (trifluoromethyl) -3-pyridazinecarboxylic acid

In an argon atmosphere, 55% iohydric acid (20 ml) was carefully added, with stirring, to a mixture of 3,6-dichloropyridazine (ABCR; 4.0g, 26.8 mmol) and sodium iodide (5, 39 g, 35.97 mmol). The reaction mixture was heated at 40 ° C for 18 h and carefully poured onto ice while stirring. Concentrated sodium hydroxide was added slowly and the mixture was stirred for 20 minutes. Then, the aqueous phase (pH> 12) was extracted with DCM and the organic phase was collected using a hydrophobic frit. The DCM phase was evaporated to provide 3

30 chloro-6-iodopyrididazine in the form of a white solid (5.99 g).

A stirred solution of methyl chlorodifluoroacetate (865 mg, 5.99 mmol) in DMF (20 ml) was treated with copper (I) iodide (855 mg, 4.49 mmol), potassium fluoride (348 mg, 5.99 mmol) and 3-chloro-6-iodopyrididazine (720 mg, 2.99 mmol) and heated at 115 ° C for 6 h. The mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate and the mixture was filtered through 35 diatomaceous earth. The aqueous phase was extracted twice with ethyl acetate and the combined extracts were dried over MgSO4. Then, the solvent was removed under reduced pressure to provide a crude product. However, chromatography on silica gel (50 g), eluting with 0-50% ethyl acetate in pentane, did not provide any of the desired products. Therefore, the DMF that had condensed in the rotary evaporator was carefully evaporated at room temperature to a volume of 2-3 ml and dissolved in ethyl acetate, washed with (x 3)

with water and dried over MgSO4. TLC on silica gel, eluting with 50% ethyl acetate in pentane, indicated a single point (Rf 0.7). Careful concentration of the solution under reduced pressure and final evaporation in a stream of argon at atmospheric pressure gave a yellow oil (0.324 g). It was shown by NMR that it was a mixture of 3-chloro-6- (trifluoromethyl) pyridazine, ethyl acetate and DMF, and was used in the next step without

5 additional purification.

A solution of impure 3-chloro-6- (trifluoromethyl) pyridazine (324 mg, 1,775 mmol) in ethanol (20 ml) was treated with palladium (II) acetate (3.99 mg, 0.018 mmol), DPPF palladium complex ( 43.5 mg, 0.053 mmol) and triethylamine (0.297 ml, 2,130 mmol), and placed in a 100 ml PAAR pressure reaction vessel. This was sealed, purged with carbon monoxide, vented and then CO was introduced at a pressure of approximately 30 bar.

10 Then, the sealed container was heated to 120 ° C (pressure raised to 40 bar). After 16 h, the vessel was cooled, the pressure was released and the mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel (10 g) and eluted with 0-30% ethyl acetate in pentane to provide ethyl 6 (trifluoromethyl) -3-pyridazinecarboxylate as a pale solid (75 mg) .

A solution of ethyl 6- (trifluoromethyl) -3-pyridazinecarboxylate (73 mg, 0.332 mmol) in ethanol (1 ml) was treated with

2M sodium hydroxide (2 ml, 4.00 mmol) and stirred overnight at room temperature. Then, the suspension was acidified by the addition of dilute hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were dried over MgSO4 and evaporated under reduced pressure to provide the title compound as a pale solid (60 mg);

m / z (ES-) 193 (M + H); LCMS Rt 1.30 min (LCMS Method 1).

20 Intermediate Product 10: 1-Methyl-2-Trifluoromethyl-5-cyanoindole

Sodium hydride (60% in mineral oil) (76 mg, 1,903 mmol) was added to 2-trifluoromethyl-1H-indole-5-carbonitrile (intermediate 20000 mg, 0.952 mmol) stirred in DMF (5 ml) in a Argon atmosphere at room temperature. The reaction mixture was stirred at room temperature for 30 min and then iodomethane (0.119 ml,

25,903 mmol). The reaction mixture was allowed to stir for an additional 1 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (50 ml). The organic extract was washed with 1: 1 water: brine (50 ml x 2), dried (MgSO4), filtered and the solvent removed to give the title compound (290 mg) which was subsequently used in the following reaction without further purification;

1H NMR (400 MHz, CDCl3): or 8.05 (1H, d), 7.59 (1H, dd), 7.46 (1H, d), 7.03 (1H, s), 3.90 ( 3H, s); m / z 225 (M + H); 30 LCMS Rt 1.13 min (LCMS Method 2).

Intermediate 11: {[1-Methyl-2- (trifluoromethyl) -1H-indole-5-yl] methyl} amine

A solution of 1-methyl-2-trifluoromethyl-5-cyanoindole (Intermediate 14, 240 mg, 1.071 mmol) in THF (10 ml) cooled to 0 ° C was treated dropwise with borane and tetrahydrofuran complex (1 M solution) (2.355 ml, 2.355 mmol) by

35 a syringe and stirred under an argon atmosphere for 24 h. The reaction mixture was quenched with methanol (5 ml) and stirred at room temperature for 10 min. The reaction mixture was evaporated to dryness to give the crude title compound as a white foam (300 mg), which was used in the next step without further purification.

Intermediate 12: 6-Bromo-N - {[2- (Trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide

A mixture of {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} amine hydrochloride (Intermediate 5, 1 g, 3.99 mmol), 6-bromo-3-pyridinecarboxylic acid (Matrix Scientific; 0.887 g, 4.39 mmol), EDC (0.841 g, 4.39 mmol), HOBT (0.672 g, 4.39 mmol) and DIPEA (2.8 ml, 16.03 mmol) in DCM (50 ml) was stirred at temperature ambient for 18 h. The mixture was stirred well with a saturated aqueous solution of NaHCO3, the organic extracts separated and the extracts.

5 aqueous were extracted further (EtOAc x 3). The combined organic extracts were dried (Phase-Sep cartridge) and evaporated under reduced pressure to give a white solid. Trituration with diethyl ether overnight and filtration produced a white crude solid (1.16 g). A portion (88 mg) was further purified by MDAP to produce the title compound as a white solid (54 mg);

10 m / z [M + H] + 396/398 (M + 1); 1H NMR (400 MHz, d4MeOD): or 8.79 (1H, d), 8.10 (1H, dd), 7.70 (1H, dd), 7.64 (1H, s), 7.42 ( 1H, d), 7.30 (1H, d), 6.86 (1H, s), 4.66 (2H, s).

(Interchangeable protons of NH (2) not visible)

Compound 1: N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (trifluoromethyl) -2-pyrimidinecarboxamide

15 2- (Trifluoromethyl) -5-pyrimidinecarboxylic acid (Bio-Farma) (108 mg, 0.560 mmol) in dichloromethane (10 ml) was stirred. Oxalyl chloride (0.082 ml, 0.934 mmol) was added and then DMF (1.808 µl, 0.023 mmol). The reaction mixture was allowed to stir for 2 h under an argon gas atmosphere. Then, the reaction mixture was evaporated to dryness and then the resulting residues were dissolved in dichloromethane (10 ml). A solution of {[2 (trifluoromethyl) -1H-indol-5-yl] methyl} amine (Intermediate 4, 100 mg, 0.467 mmol) in DCM (10 ml) was added and then added

20 triethylamine (0.135 ml, 0.934 mmol). The reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was evaporated to dryness. Then, the resulting residues were purified in the MDAP to give the title compound (105 mg). m / z (ES +) 389 (M + 1); 1H NMR (400 MHz, d6-DMSO): o 12.24 (1H, s), 9.57 (1H, t), 9.43 (2H, s), 7.68 (1H, s), 7, 45 (1H, d), 7.32 (1H, dd), 7.00 (1H, s), 4.63 (2H, d).

Compound 2: N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (chloro) -2-pyrimidinecarboxamide

2-Chloro-pyrimidin-5-carboxylic acid (209 mg, 1,317 mmol) in dichloromethane (20 ml) was stirred. Oxalyl chloride (0.210 ml, 2.394 mmol) and then DMF (4.63 µl, 0.060 mmol) was added. The reaction mixture was allowed to stir for 2 h under an argon gas atmosphere. Then, the reaction mixture was evaporated to dryness and then the resulting residues were dissolved in dichloromethane (20 ml). A solution of {[2- (trifluoromethyl) -1H-indole was added

5-yl] methyl} amine (Intermediate 4, 300 mg, 1,197 mmol) in DCM (10 ml) and then triethylamine (0.500 ml, 3.59 mmol) was added. Then, the reaction mixture was allowed to stir at room temperature for 24 h. The reaction mixture was evaporated to dryness. Then, the resulting residues were partitioned between 2M HCl (50 ml) and ethyl acetate (50 ml). The organic layer was collected, dried (MgSO4), filtered and the solvent removed. Then, the resulting residues were purified in the MDAP to give the title compound (240 mg);

35 m / z (ES-) 353 and 355 (M-1); 1H NMR (400 MHz, d6-DMSO): or 12.24 (1H, s), 9.43 (1H, t), 9.16 (2H, s), 7.65 (1H, s), 7, 45 (1H, d), 7.31 (1H, dd), 7.00 (1H, s), 4.60 (2H, d).

Compound 3: 6- [3- (Ethyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} -3-pyridinecarboxamide

To a stirring solution of HATU (72.8 mg, 0.192 mmol) in DMF (1 ml) was added 6- [3- (ethyloxy) phenyl] -3-pyridinecarboxylic acid (Intermediate 6, 29 mg, 0.119 mmol) in DMF (0.5 ml), followed by DIPEA (0.050 ml, 0.287 mmol) and finally {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} amine (Intermediate 4.24 mg, 0.096 mmol) in DMF (1 ml). The solution

5 stirred for 24 h. The DMF was removed using a rotary evaporator, followed by the addition of a solution of DCM and sodium bicarbonate. The mixture was poured through a phase separation cartridge. The organic layer was evaporated to dryness and purified using MDAP to give the title compound as a white solid (27 mg);

m / z [M + H] + 440 (M + 1); 1H-NMR (400 MHz, MeOD): or 9.06 (1H, s), 8.28-8.30 (1H, m), 7.93-7.95 (1H, m), 7.67 ( 1H, s), 10 7.55-7.59 (2H, m), 7.32-7.45 (3H, m), 7.00-7.03 (1H, m), 6.86 (1H , s), 4.69 (2H, s), 4.12 (2H, c), 1.42 (3H, t).

Compound 4: 5- (Methyloxy) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} -2-pyrazinecarboxamide

To a stirred solution of HATU (121 mg, 0.319 mmol) in DMF (1 ml) was added 5- (methyloxy) -2pyrazinecarboxylic acid (AniChem LLC; 49.2 mg, 0.319 mmol) in DMF (0.5 ml) , followed by DIPEA (0.084 ml, 0.479 mmol)

15 and finally {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} amine (Intermediate 4.40 mg, 0.165 mmol) in DMF (1 ml). The solution was stirred for 24 h. The DMF was removed using a rotary evaporator, followed by the addition of a solution of DCM and sodium bicarbonate. The mixture was poured through a phase separation cartridge. The organic layer was evaporated to dryness and purified using MDAP to give the title compound as a white solid (34 mg);

20 m / z [M + H] + 351 (M + 1); 1H-NMR (400 MHz, MeOD): or 8.82 (1H, s), 8.20 (1H, s), 7.63 (1H, s), 7.40-7.42 (1H, m) , 7,297.31 (1H, m), 6.84 (1H, s), 6.67 (2H, s), 4.03 (3H, s).

Compound 5: 6- (Phenyloxy) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide

To a stirred solution of HATU (121 mg, 0.319 mmol) in DMF (1 ml) was added 6- (phenyloxy) -3 acid

Pyridinecarboxylic acid (Maybridge; 51.5 mg, 0.239 mmol) in DMF (0.5 ml), followed by DIPEA (0.084 ml, 0.499 mmol) and finally {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} amine (Intermediate 4.40 mg, 0.165 mmol) in DMF (1 ml). The solution was stirred for 24 h. The DMF was removed using a rotary evaporator, followed by the addition of a solution of DCM and sodium bicarbonate. The mixture was poured through a phase separation cartridge, the organic phase was evaporated to dryness and purified using MDAP to give the title compound as a colored solid.

30 white (11 mg);

m / z [M + H] + 412 (M + 1); 1H-NMR (400 MHz, MeOD): or 8.61 (1H, s), 8.22-8.25 (1H, m), 7.63 (1H, s), 7.41-7.45 ( 3H, m), 7.22-7.31 (2H, m), 7.11-7.14 (2H, m), 6.85-6.99 (1H, m), 6.86 (1H, s), 4.65 (2H, s).

Compound 6: 2- [3- (Ethyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} -5-pyrimidinecarboxamide

To a stirring solution of HATU (30.3 mg, 0.080 mmol) in DMF (1 ml) was added 2- [3- (ethyloxy) phenyl] -5-pyrimidinecarboxylic acid (Intermediate 7, 10 mg, 0.041 mmol) in DMF (0.5 ml), followed by DIPEA (0.021 ml, 0.120 mmol) and finally {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} amine (Intermediate 4.10 mg, 0.040 mmol) in DMF (1 ml). The solution

5 was stirred for 24 h and then the DMF was removed using a rotary evaporator. Then, DCM and a solution of sodium bicarbonate were added to the residue. The mixture was poured through a phase separation cartridge, the organic phase was evaporated to dryness and purified using MDAP to give the title compound as a yellow solid (8 mg);

m / z [M + H] + 441 (M + 1); 1H-NMR (400 MHz, MeOD): or 9.16-9.26 (assumed 2H, m), 8.01-8.06 (2H, m), 7.68 (1H, s), 10 7, 33-7.45 (3H, m), 7.07-7.10 (1H, m), 6.87 (1H, s), 4.70 (2H, s), 4.10-4.15 ( 2H, c), 1.42 (3H, t).

Compound 7: N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (4-methylpiperidin) -2-pyrimidinecarboxamide

To a stirred solution of HATU (34.4 mg, 0.090 mmol) in 1 ml of DMF was added (2- (4-methyl-1-piperidinyl) 5-pyrimidinecarboxylic acid) (Matrix Scientific, 20 mg, 0.090 mmol) in 0.5 ml DMF, followed by DIPEA (0.016 ml, 0.090

15 mmol) and finally {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} amine (Intermediate 4, 22.66 mg, 0.090 mmol) in 1 ml of DMF. Stirring was continued for 16 hours. A 1M solution of citric acid (10 ml) was added and then the mixture was extracted with ethyl acetate (20 ml). Then, the organic extract was washed with a 1M solution of citric acid (10 ml) and brine (10 ml), dried (MgSO4), filtered and evaporated to dryness. Then, the resulting residues were purified in MDAP to dryness to give the title compound (19 mg);

20 m / z (ES +) 418 (M + 1); 1H NMR (400 MHz, d6-DMSO): or 12.20 (1H, s), 8.89 (1H, t), 8.79 (2H, s), 7.59 (1H, s), 7, 43 (1H, d), 7.27 (1H, dd), 6.99 (1H, s), 4.71-4.68 (2H, m), 4.53 (2H, d), 2.98 -2.88 (2H, m), 1.71-1.60 (3H, m), 1.09-0.97 (2H, m), 0.92 (3H, d).

Compound 8: 4- (1H-Pirazol-3-yl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide

To a solution of HATU (0.200 mmol) in DMF (0.5 ml) was added 4- (1 H -pyrazol-3-yl) benzoic acid (Apollo Scientific Ltd.) (0.12 mmol) in DMF (0 , 5 ml), followed by DIPEA (0.300 mmol) and finally {[2- (trifluoromethyl) -1Hindole-5-yl] methyl} amine (Intermediate 4, 0.025 g, 100 µmol) in DMF (0.25 ml). The experiment was performed in series using a Bohdan miniblock. The block was stirred for 24 hours. The compound was purified using an aminopropyl column that was preconditioned with DMF. The column was washed with DMF (x 2). The washes are

30 evaporated to dryness and then the resulting residue was purified with MDAP to give the title compound;

m / z [M + H] + 385 (M + 1); 1H-NMR (400 MHz, MeOD): or 7.99 (1H, s), 7.87-7.95 (4H, m), 7.72 (1H, s), 7.67 (1H, s) , 7.44 (1H, d) 7.33 (1H, d), 6.96 (1H, s), 6.77 (1H, s), 4.66 (2H, s).

The following compounds were prepared by a procedure similar to that described for Compound 8 using the appropriate carboxylic acid with 2- (trifluoromethyl) -1H-indole-5-yl] methyl} amine hydrochloride (Intermediate 4):

Comp.

Rb m / z [M + H] + Retention time (min) LCMS method 1

9

478 3.29

10

402 3.18

eleven

386 2.73

12

386 2.78

13

431 3.06

The following compounds were prepared by a procedure similar to that described for Intermediate 12 using the appropriate carboxylic acid with 2- (trifluoromethyl) -1H-indole-5-yl] methyl} amine hydrochloride (Intermediate 5):

Comp.

R3 m / z [M + H] + Retention time (min) LCMS method 1

14

387 2.19

fifteen

386 2.50

16

396 1.86

17

396 2.68

18

353/355 (M-H) 2.71

Compound 19: 6- (Trifluoromethyl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} -3-pyridazinecarboxamide

A solution of 6- (trifluoromethyl) -3-pyridazinecarboxylic acid (Intermediate 9, 60 mg, 0.312 mmol), HATU (131 mg,

5,344 mmol) and DIPEA (0.164 ml, 0.937 mmol) in acetonitrile (3 ml) was stirred at room temperature under an argon atmosphere for 15 min and then treated with {[2- (trifluoromethyl) -1H-indole hydrochloride -5il] methyl} amine (Intermediate 5.78 mg, 0.312 mmol). The reaction mixture was stirred for 18 h and evaporated under reduced pressure to remove acetonitrile. The residue was dissolved in DCM and washed with water. The organic solution was dried over MgSO4 and evaporated under reduced pressure to provide the crude product, which was purified by

10 MDAP to give the title compound (39 mg) as a pale solid;

m / z (ES-) 387 (M-H); 1H NMR (400 MHz, CDCl3) 8.56 (1H, d), 8.50 (1H, sa), 8.48 (1H, sa), 8.03 (1H, d), 7.70 (1H, s), 7.43 (1H, d), 7.35 (1H, d), 6.91 (1H, s), 4.84 (2H, d) ppm.

Compound 20: 6- [2- (Methyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} -3-pyridinecarboxamide

A mixture of 6-bromo-N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide (Intermediate 12, 80 mg, 0.201 mmol), [2- (methyloxy) acid phenyl] boronic (Sigma-Aldrich; 46 mg, 0.303 mmol) and cesium carbonate (131 mg, 0.402 mmol) in DME (4 ml) and water (1 ml) was degassed by bubbling argon through it for 5 min. Tetrakis (triphenylphosphine) palladium (0) (25 mg, 0.022 mmol) was added and the mixture was heated in a microwave reactor at 100 ° C for 30 min. The mixture was partitioned between EtOAc and water, and the organic extracts were dried (through Phase

20 Sep with a little Na2SO4) and evaporated under reduced pressure. The residue was purified using MDAP to produce the title compound as an off-white solid (31 mg).

m / z [M + H] + 426 (M + 1); 1H NMR (400 MHz, d4MeOD): or 9.05 (1H, d), 8.24 (1H, dd), 7.92 (1H, d), 7.67 (1H, s), 7.65 ( 1H, d), 7.41-7.48 (2H, m), 7.34 (1H, d), 7.12 (1H, d), 7.05 (1H, t), 6.86 (s , 1H), 4.70 (2H, s), 3.86 (3H, s). (Interchangeable protons of NH (2) not visible)

The following compounds were prepared by a procedure similar to the procedure described for the

Compound

using he acid  boronic suitable  with 6-Bromo-N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} -3

pyridinecarboxamide

(Intermediate 12)  or 5-chloro-N - {[2- (trif luoromethyl) -1H-indole-5-yl] methyl} -2-pyrazinecarboxamide

(Compound 18):

Comp.

R3 m / z [M + H] + Retention time (min) LCMS method 1

twenty-one

439 (M-H) 3.21

22

396 (M-H) 2.29

Compound 23: N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (N'N Dimethyl) -2-pyrimidinecarboxamide

Sodium metal (45.4 mg, 1,973 mmol) was dissolved in 2,2,2-trifluoroethanol (0.288 ml, 3.95 mmol) to give a

10 freshly prepared solution of sodium 2,2,2-trifluoroethoxide which was then added to a stirred solution of N - [(2trifluoromethyl-1 H-indol-5-yl) methyl] -5- (chloro) -2-pyrimidinecarboxamide ( Compound 2, 70 mg, 0.197 mmol) in DMF (2 ml). Then, the reaction mixture was heated at 100 ° C for 30 min. The reaction mixture was allowed to cool to room temperature and was quenched with water (10 ml). The mixture was extracted with ethyl acetate (20 ml) and the organic extract was washed with a 1: 1 mixture of water: brine (2 x 10 ml), dried (MgSO4), filtered and the solvent was

15 withdrew. The resulting residues were purified by MDAP and evaporated to dryness to give the title compound as a white solid (40 mg). It is believed that the addition of the dimethylamine group resulted from the decomposition of the DMF under the reaction conditions;

m / z (ES +) 364 (M + 1); 1H NMR (400 MHz, d6-DMSO): or 12.21 (1H, s), 8.89 (1H, t), 8.80 (2H, s), 7.60 (1H, s), 7, 43 (1H, d), 7.28 (1H, dd), 7.00 (1H, s), 4.60 (2H, d), 3.17 (6H, s).

Compound 24: N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (2,2,2-trifluoroethoxy) -2-pyrimidinecarboxamide

N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (chloro) -2-pyrimidinecarboxamide (Compound 2, 100 mg, 0.282 mmol) in 2,2,2-trifluoroethanol (5 ml) Then, a freshly prepared solution of sodium 2,2,2-trifluoroethoxide (60% sodium hydride in mineral oil (226 mg, 5.64 mmol) in 2,2,2-trifluoroethanol (5 ml)) was added to the solution. reaction mixture.

5 Then, the reaction mixture was heated at 85 ° C for 30 min. The reaction mixture was allowed to cool to room temperature and then evaporated to dryness. The resulting residues were partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was collected, dried (MgSO4), filtered and the solvent removed. The resulting residues were purified by MDAP and evaporated to dryness to give the title compound as a white solid (90 mg);

10 m / z (ES +) 419 (M + 1); 1H NMR (400 MHz, d6-DMSO): o 12.25 (1H, s), 9.29 (1H, t), 9.11 (2H, s), 7.65 (1H, s), 7, 45 (1H, d), 7.30 (1H, dd), 7.00 (1H, s), 5.12 (2H, m), 4.59 (2H, d).

Compound 25: N - [(1-Methyl-2-Trifluoromethylindole-5-yl) methyl] -5- (trifluoromethyl) -2-pyrimidinecarboxamide

2- (Trifluoromethyl) -5-pyrimidinecarboxylic acid (Bio-Farma; 152 mg, 0.789 mmol) in DCM (10 ml) was stirred. After,

Oxalyl chloride (0.115 ml, 1.315 mmol) and DMF (0.509 µl, 6.57 µmol) were added. The reaction mixture was allowed to stir for 2 h under an argon atmosphere. Then, the reaction mixture was evaporated to dryness and the resulting residues were dissolved in DCM (10 ml). A solution of [(1-methyl-2-trifluoromethylindole-5-yl) methyl] amine (Intermediate 11, 150 mg, 0.657 mmol) in DCM (10 ml) was added, followed by triethylamine (0.183 ml, 1.315 mmol). Then, the reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture is

20 quenched with methanol (10 ml) and evaporated to dryness. Then, the resulting residues were partitioned between ethyl acetate and a 1M solution of citric acid. The organic layer was collected, dried (MgSO4), filtered and the solvent removed. The resulting residues were purified by MDAP and evaporated to dryness to give the title compound (90 mg);

m / z (ES-) 401 (M-1); 1H NMR (400 MHz, d6-DMSO): or 9.60 (1H, t), 9.44 (2H, s), 7.70 (1H, s), 7.63 (1H, d), 7, 40 (1H, 25 dd), 7.10 (1H, s), 4.65 (2H, d), 3.86 (3H, s).

Biological test

The PAM activity of the compounds of the invention in a7 nAChR can be determined using the following cell-based calcium flow assay using a Fluorometric Image Plate Reader (FLIPR) (see Schroeder et al .; J. Biomolecular Screening , 1 (2), p75-80, 1996).

The stably transfected GH4C1 cell line was suspended with human a7 nAChR in a 384 well plate and incubated at 30 ° C for 48 h in a 5% carbon dioxide atmosphere. The growth medium was removed and the cells were washed three times with a balanced Hank salt solution (HBSS), 20 mM HEPES and 2.5 mM probenecid leaving 20 µl of wash solution in each well. A filler solution (20 µl) containing HBSS, probenecid, Fluo4 AM 1--4 µM (a calcium indicator dye) and pluronic acid and plate was added

35 was incubated for 45 min at 37 ° C in an atmosphere without carbon dioxide. The cells were washed three times leaving 30 µl in each well. The plate containing the cells and the calcium indicator dye was then transferred to FLIPR. The test was started by collecting baseline data points at 10-second intervals followed by the addition of the test compound in buffer solution (0.33% DMSO) and diluted to a final concentration of 10 µM and serial dilution of the wells, 1: 2 or 1: 3, gave a low concentration of <1 nM. After 5-10 more minutes

40 µl of 50 µM nicotine was added and the data was collected for 2-3 minutes. Nicotine produced a rapid, transient and reproducible calcium flow that could be enhanced with positive allosteric modulating test compounds.

The support compounds were selected using the assay described above and gave a pCE50 value equal to or greater than 5.0 with a maximum potentiation of the response area at approximately 1200% with respect to the nicotine control.

In vivo assays with utility for the evaluation of the activity of positive modulators of the nicotinic a7 receptor include, but are not limited to: cognition tests in both virgin and pharmacologically affected animals including delayed alternation and non-alternation, passive avoidance, object recognition

5 new, Morris water maze (or variants thereof), radial maze, reaction time task before a stimulus in series of five elements, conditioning auditory / contextual fear; sensory inhibition assays in both virgin animals and pharmacologically affected animals including suppression of the startle reflex by a pre-stimulus and auditory inhibition; and drug-induced locomotor activity assays (eg, amphetamine, morphine, phencyclidine).

Claims (11)

1. A compound of List A N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (trifluoromethyl) -2-pyrimidinecarboxamide; N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (chloro) -2-pyrimidinecarboxamide; 6- [3- (Ethyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 5- (Methyloxy) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -2-pyrazinecarboxamide; 6- (Phenyloxy) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 2- [3- (Ethyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -5-pyrimidinecarboxamide; N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (4-methylpiperidin) -2-pyrimidinecarboxamide; 4- (1H-Pirazol-3-yl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide; 4- [4-Cyano-5- (trifluoromethyl) -1 H -pyrazol-1-yl] -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide; 4- (1,3-Thiazol-2-yl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide; 4- (4H-1,2,4-Triazol-4-yl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide; 4- (1H-1,2,4-Triazol-3-yl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide; 4- (6-Chloro-3-pyridazinyl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} benzamide; 6- (1H-1,2,4-Triazol-1-yl) -N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} -3-pyridinecarboxamide; 6- (1H-Pirazol-1-yl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; N - {[2- (Trifluoromethyl) -1H-indol-5-yl] methyl} -2,3'-bipyridin-5-carboxamide; 6-Phenyl-N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 5-Chloro-N - {[2- (trifluoromethyl) -1H-indole-5-yl] methyl} -2-pyrazinecarboxamide; 6- (Trifluoromethyl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridazinecarboxamide; 6- [2- (Methyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -3-pyridinecarboxamide; 5- [3- (Ethyloxy) phenyl] -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -2-pyrazinecarboxamide; 5- (3-Pyridinyl) -N - {[2- (trifluoromethyl) -1H-indol-5-yl] methyl} -2-pyrazinecarboxamide; N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (N'N Dimethyl) -2-pyrimidinecarboxamide; N - [(2-Trifluoromethyl-1H-indol-5-yl) methyl] -5- (2,2,2-trifluoroethoxy) -2-pyrimidinecarboxamide; N - [(1-Methyl-2-Trifluoromethylindole-5-yl) methyl] -5- (trifluoromethyl) -2-pyrimidinecarboxamide; or a salt thereof.

2.

 The salt according to claim 1, wherein the salt is a pharmaceutically acceptable salt.

3.

 A compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, for use as a medicament.

Four.

 A compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, for use in the treatment of a psychotic disorder.

5.

 The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein the psychotic disorder is schizophrenia.

6.

 A compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, for use in the treatment of cognitive impairment.

7.

 Use of a compound as or defined in claim 1 or a pharmaceutically acceptable salt of the

same, in the manufacture of a medicine for the treatment of a psychotic disorder.

8.

 The use according to claim 7, wherein the psychotic disorder is schizophrenia.

9.

 Use of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cognitive impairment.

10.

 A pharmaceutical composition comprising a) a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, and b) one or more pharmaceutically acceptable carriers or excipients.

eleven.

 A combination comprising a) a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof and b) an additional active ingredient.